Thermal biology is different between small and large mammals. At typical ambient environmental temperature (eg., 22 C), over one third of energy expenditure in mice is devoted to maintaining core body temperature, largely by brown adipose tissue (BAT). To conserve energy, mice can enter a regulated hypothermia, while humans do not. Since humans expend little or no energy specifically to keep warm, mice studied at 30 C (near thermoneutrality) may be a better model for human energy homeostasis. In mice, dinitrophenol, a protonophore, and CL316243, a beta3-adrenergic agonist, both increased metabolic rate at thermoneutrality but only CL316243 increased it at 22 C. Mice housed at 30 C also may become more obese than mice at 22 C. The effect of environmental temperature must be understood to ensure applicability of mouse experiments to human obesity. BAT is also intimately involved with hypothermia, as induction of hypothermia involves complete inactivation of BAT, while recovery reactivates it. Thus, studies of drugs causing hypothermia should interact in the neural pathways that contribute to the regulation and control of BAT. Progress in FY2019 includes the following: We reported that acute activation of Brs3-expressing neurons in the dorsomedial hypothalamus (DMHBrs3) increased body temperature, brown adipose tissue temperature, energy expenditure, heart rate, and blood pressure, with no effect on food intake or physical activity. Conversely, activation of Brs3 neurons in the paraventricular nucleus of the hypothalamus had no effect on Tb or energy expenditure, but suppressed food intake. Inhibition of DMHBrs3 neurons decreased Tb and energy expenditure, suggesting a necessary role in Tb regulation. We found that the preoptic area provides major input (excitatory and inhibitory) to DMHBrs3 neurons. Optogenetic stimulation of DMHBrs3 projections to the raphe pallidus increased Tb. Thus, DMHBrs3raphe pallidus neurons regulate Tb, energy expenditure, and heart rate, and Brs3 neurons in the paraventricular nucleus of the hypothalamus regulate food intake. Brs3 expression is a useful marker for delineating energy metabolism regulatory circuitry. In a human study collaboration, we reported that lean men have a limited ability to increase energy expenditure in the cold (averaging 17%), while obese men have less (averaging 6%).